Amvuttra to treat polyneuropathy of hereditary

transthyretin-mediated amyloidosis
 

Prepared by: Reem Al-zawahreh

Project Supervisor: Dr. Naim kittaneh
Outline
• Introduction.
• The pathophysiology of the neuropathy.
• The main classifications of hereditary amyloidosis diseases.
• ATTR amyloidosis.
• Symptoms of disease.
• Diagnosis of disease.
• Non-TTR amyloidosis.
• Symptoms of disease.
• Treatment of disease.
• Conclusions.
:Introduction

  polyneuropathy of hereditary transthyretin-mediated

amyloidosis:
is a condition with adult-onset caused by mutation of the transthyretin
(TTR) and characterized by extracellular deposition of amyloid and
destruction of the somatic and autonomic PNS, leading to loss of
autonomy and death.
The pathophysiology of the polyneuropathy:

Instability and proteolysis of mutant TTR

The main classifications of hereditary amyloidosis diseases:

Amyloidosis disease

Non-TTR amyloidosis ATTR amyloidosis

 ATTR amyloidosis:

A rare, progressive disease

characterized by the abnormal
buildup of amyloid deposits
composed of misfolded transthyretin
protein in the body's organs and
tissues.
Symptoms of disease:
Diagnosis of disease:

.a patient is tested to determine if they have amyloid proteins in their body

.The main diagnostic testing for any amyloidosis disease includes blood tests, urine tests and biopsies

.Blood and urine tests will be done to help your doctor determine the diagnosis of amyloidosis

a tissue biopsy will be performed. This involves the removal of a small sample of tissue for lab
.examination

after amyloidosis is confirmed and it is determined that there is transthyretin amyloid protein, the
.protein needs to be identified by protein sequence analysis and DNA sequencing must be performed
 Non-TTR amyloidosis:

These diseases are considered rarer

than the ATTR variation and consist of
other inherited gene mutations that
also cause major symptoms and affect
.health
 Symptoms of disease: 
• The symptoms, as well as the prognosis, depending on the tissue and organ(s)
affected by the amyloid deposits.

Apolipoprotein Apolipoprotein
 Fibrinogen Aa Gelsolin Cystatin C
 AI AII

kidney kidneys kidney symptoms only hemorrhage complications

neuropathy symptoms
liver neuropathy Eye
heart
peripheral neuropathy
cutaneous (skin) areas
laryngeal (larynx)
Risk Factors:
Management of disease:
 Tafamidis
is a medication used to treat transthyretin-
mediated amyloidosis.

 Mechanism of action:
binding and stabilization of the TTR tetrameric
form, reducing the likelihood of dissociation into
monomers, and thus reducing amyloid fibril
formation and deposition.

 Dosage and Administration:

is administered via 80 mg (four 20 mg capsules)
once a day.
• Contraindications: • Adverse effects:
 None.

• Warnings and precautions:

 Using this medicine while you are pregnant
can harm an unborn baby.
 Diflunisal
A nonsteroidal anti-inflammatory drug used for
Transthyretin amyloidosis cardiomyopathy (ATTR-CM)
 Mechanism of action:
can stabilize the TTR tetramer in vitro and may prevent
misfolding monomers and dimers from forming amyloid
deposits in the heart.
 Dosage and Administration:
(125, 250, or 500 mg bid) oral administration.
• Contraindications: • Adverse effects:
 is contraindicated in patients with
known hypersensitivity to diflunisal or • signs of an allergic reaction.
the excipient. • severe skin reaction.
• changes in vision.
• Warnings and precautions:
• Rapid weight gain.
 increase risk of fatal heart attack or • ringing in your ears.
stroke.
 may also cause stomach or intestinal
bleeding, which can be fatal.
 Patisiran:
 Mechanism of action:

 was approved by the FDA on August 10, 2018,

for the treatment of hATTR amyloidosis with
polyneuropathy.
• Dosage and Administration:
 is administered via intravenous (IV) infusion. Dosing is based on actual body weight.

 For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3
weeks.

 For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3
weeks.
• Contraindications: • Adverse effects:
 None.

• Warnings and precautions:

 Patisiran treatment leads to a decrease in
serum vitamin A levels.
 Inotersen:

 was approved by the FDA on Oct 5, 2018, for

the treatment of hATTR amyloidosis with
polyneuropathy.

 Mechanism of action:
Antisense oligonucleotide that causes degradation of
mutant and wild-type transthyretin (TTR) mRNA through
binding to the TTR mRNA, which results in a reduction of
serum TTR protein and TTR protein deposits in tissues
• Dosage and Administration:
 Adults—284 milligrams (mg) injected under the skin once a week.

 Inotersen is for subcutaneous use only and should be administered by a

healthcare professional.
• Contraindications: • Adverse effects:
 Platelet count below 100 x 109/L .

 History of acute glomerulonephritis caused by

inotersen.
 History of a hypersensitivity reaction to inotersen

• Warnings and precautions:

 reductions in platelet count that may result in
sudden and unpredictable thrombocytopenia that
can be life-threatening.
 Three Inotersen-treated patients (3%) had sudden
severe thrombocytopenia
New treatment:

: ™AMVUTTRA
contains vutrisiran, a chemically modified double-
stranded small interfering ribonucleic acid (siRNA)
that targets mutant and wild-type transthyretin
(TTR)
 Mechanism of action

is designed to bind to TTR mRNA, triggering a process called RNA

interference that promotes mRNA destruction. Without a functional RNA
.template, the production of the faulty transthyretin protein
• Dosage and Administration: • Dosage Form and strengths:

 Injection: 25 mg/0.5 mL in a single-dose

The recommended dosage of AMVUTTRA is
25 mg administered
.prefilled syringe

 by subcutaneous injection once every 3

months. (2.1)
 AMVUTTRA is for subcutaneous use only
and should be administered by a healthcare
professional.
Pharmacokinetics
Pharmacodynamics

Administration of the recommended

AMVUTTRA dosage every 3 months to
patients with hATTR amyloidosis, vutrisiran
reduced mean serum TTR at steady-state by
.83%

Similar TTR reductions were observed

regardless of Val30Met genotype status,
.weight, sex, age, or race

Vutrisiran also reduces steady -state serum

.vitamin A by 62% over 9 months
 • Adverse reactions:
• Contraindications:
 None.
• Warnings and precautions:
 Reduced serum vitamin A levels.

Supplement with the recommended

daily allowance of vitamin A
• Pregnancy:
supplementation is advised for patients taking
AMVUTTRA. Vitamin A is essential for normal
embryofetal development; however, excessive
levels of vitamin A are associated with adverse
developmental effects.
The effects on the fetus of a reduction in
maternal serum TTR caused by AMVUTTRA and
of vitamin A supplementation are unknown .
• Lactation :
There is no information regarding the
presence of vutrisiran in human milk, the
effects on the breastfed infant, or the
.effects on milk production
• Pediatric Use:
Safety and effectiveness in pediatric
.patients have not been established
• Geriatric Use: • Hepatic Impairment:
No dose adjustment is required in patients No dose adjustment is recommended in
≥65 years of age . .patients with mild hepatic impairment
• Drug Interaction Studies:
• Renal Impairment: No clinical drug-drug interaction studies have been
performed with vutrisiran. In vitro studies suggest
No dose adjustment is recommended in that vutrisiran is not a substrate or inhibitor of
patients with mild or moderate renal .cytochrome P450 enzymes
impairment.
Vutrisiran is not expected to cause drug-drug
interactions by inducing CYP enzymes or
modulating the activities of drug transporters
ON CLINICAL TOXICOLOGY :

• Carcinogenesis
Carcinogenicity studies of vutrisiran have not been conducted.
• Mutagenesis
Vutrisiran was negative for mutagenicity in vitro (bacterial
mutagenicity, chromosomal aberration in human blood peripheral
lymphocytes) and in vivo (rat bone marrow micronucleus) assays.
• Impairment of Fertility
Subcutaneous administration of vutrisiran (0, 15, 30, or 70
mg/kg/week) to male and female rats prior to and during mating and
continuing in females to gestation day 6 resulted in no adverse
effects on fertility or reproductive performance.
 Syringe Appearance

Before use After use

 Preparation and Administration:
:Prepare the syringe
.If stored cold, allow the syringe to warm to room temperature for 30 minutes prior to use
.Remove the syringe from the packaging by gripping the syringe body

:Choose and prepare the injection site

Abdomen, thigs, upper arm

:Prepare the syringe for injection

Hold the syringe body with one hand 2. Pull the needle cap straight .1
Off with the other hand 3. dispose of needle cap immediately

:Perform the injection

.Pinch the cleaned skin .1
Fully insert the needle into the pinched skin at a 45°-90° angle .2
.Push the plunger rod as far as it will go to administer the dose and activate the needle shield .3
.Release the plunger rod to allow the needle shield to cover the needle .4
 Conclusions:

 TTRv amyloidosis is the most severe hereditary polyneuropathy of adult-

onset.
 TTR gene testing can be used to rule out ATTRv amyloidosis and should be
performed early if the condition is suspected.
 The dissociation of mutant TTR homotetramers into monomers, the
disruption of the blood-nerve barrier, and the misfolding and subsequent
aggregation of TTR are major events in the pathogenesis of neuropathy.
 The therapeutic arsenal has widened to include liver transplantation, TTR
stabilizers, and TTR gene silencers. Most patients should benefit from active
treatment regardless of the stage of their disease. However, the abilities of
these treatments to slow or reverse the disease and their safety differ.